Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
The EP patent 457559 described the process for the preparation of duloxetine comprises of using alkali metal hydride like sodium hydride, which is commercially not recommendable.
The U.S. Pat. No. 5,362,886 described the process for the preparation of (+)Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine phosphoric acid salt and preparation of hydrochloride salt using aqueous hydrochloric acid and ethyl acetate as a solvent.
The U.S. Pat. No. 5,023,269 claims Duloxetine and its pharmaceutically acceptable salts and method of treating anxiety and obesity. The patent also discloses the processes for the preparation of Duloxetine and its pharmaceutically acceptable salts, however the patent not disclosed the process for the preparation of hydrochloride salt.
The EP patent 0650965 B1 discloses the process for the preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine an intermediate of Duloxetine which was isolated as a phosphoric acid salt and disclosed the process for the preparation of Duloxetine hydrochloride using aqueous hydrochloric acid and ethyl acetate as a solvent.
The U.S. Pat. No. 5,491,243 and U.S. Pat. No. 5,362,886 discloses the stereospecific process for the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine and claimed the same. In both the patents the above said compound isolated as a phosphoric acid salt.
Like any chemical compound, duloxetine hydrochloride can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine hydrochloride or any active pharmaceutical ingredient are undesirable, and in extreme cases, might even be harmful to a patient being treating with a dosage form of the active pharmaceutical ingredient in which a sufficient amount of impurities is present. Furthermore, the undesired enantiomeric impurities reduce the sufficient level of active pharmaceutical ingredient present in the pharmaceutical composition.
It is also known in the art that impurities in an active pharmaceutical ingredient may arise from degradation of the active pharmaceutical ingredient itself, which is related to the stability of the pure active pharmaceutical ingredient during storage, and the manufacturing process, including chemical synthesis. Process impurities which include unreacted starting materials, chemical derivatives of impurities contained in the starting materials, synthetic by-products, and degradation products.
In addition to stability, which is factor in the shelf life of the active pharmaceutical ingredient, the purity of the active pharmaceutical ingredient in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for active pharmaceutical ingredient manufacturers requires that process impurities be maintained below set limits by specifying the quality raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during the preparation process, it should be analyzed for the purity by HPLC or TLC analysis to determine if it is desirable for continue the process or need to purified further to continue the process especially for use in a pharmaceutical product. The active pharmaceutical ingredient need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather the purity standards are set with the intension of ensuring that an active pharmaceutical ingredient is as free of impurities as possible, and thus, is as safe as possible for clinical use.
Duloxetine hydrochloride prepared as per the prior art process containing the isomer impurity (+)-N-methyl-3(1-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as “DU-I” (represented below) and other undesired isomer i.e., R-isomer of Duloxetine hydrochloride.

The impurity “DU-I” is formed due to the carry over of isomer, i.e., 3-acetyl thiophene compound of formula 2I as an impurity present in 2-acetyl thiophene compound of formula 2. The formation of isomer “DU-I” during the preparation of duloxetine hydrochloride schematically represented in scheme-1, in which the Formula-4I, 5I, 6I and 8I represents the corresponding derivatives of isomer impurity formation in each stage.

The international patent publication WO 2006/099433 disclosed the process for the purification of duloxetine hydrochloride to reduce the (+)-N-methyl-3-(1-napthalenyloxy)-3(3-thineyl) propanamine isomer impurity i.e. “DU-I”. The said patent disclosed the process for the purification of Duloxetine hydrochloride to reduce the level of said isomer content. Generally purification at the final stage of any compound leads to loss of material which increases cost of production which is not recommended for commercial scale-up.
We, the present inventors found the origin of isomer impurity (“DU-I”) formation (represented in scheme-1) is due to the presence of 3-acetyl impurity in the starting material 2-acetyl compound of formula-2.
When we were working to eliminate the “DU-I” impurity in the origin itself, surprisingly found that the purity of Duloxetine hydrochloride has been increased by employing purification at first stage. The purification of compound of formula-4, then usage of this pure intermediate in the preparation of Duloxetine hydrochloride gives high pure Duloxetine hydrochloride which is free from the said isomer impurity. Purification of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol in a suitable solvent to eliminate the corresponding derivative of R-isomer in an early stage. By employing purification at the initial stages instead of final stage avoids the usage of high inputs of raw materials, which avoids increase in cost of production.
The main objective of the present invention is to provide an improved process for the preparation of high pure Duloxetine hydrochloride substantially free from impurities such as (+)-N-methyl-3-(1-napthalenyloxy)-3(3-thineyl) propanamine impurity (“DU-I”) and undesired (R)-isomer of Duloxetine hydrochloride.